Malignant pleural mesothelioma (MPM) is a lethal malignancy of the pleura for which there is little effective therapy and overall survival remains dismal. This cancer affects approximately 3,000 Americans per year and its incidence is rising. Classification and staging is difficult because there are four different staging systems and the correct histological subtype of MPM is often difficult to diagnose. In addition, there are no known diagnostic or prognostic markers for MPM and limited knowledge of gene expression in this malignancy. In preliminary experiments, we have used oligonucleotide-based microarrays to evaluate gene expression in MPM and confirmed the results using real time quantitative PCR. We have developed a new gene ratio based model that correlates with outcome after surgical resection for MPM independently from stage, histologic subtype and any other known clinical predictor. We have demonstrated that this simple test can be performed by quantitative real time RT-PCR and correctly classified two cohorts of MPM specimens based on outcome. The goal of this proposal is to first confirm and refine the prognostic gene-ratio test that we discovered for MPM by comparing it to several others such tests. We will then determine the reproducibility, precision and variability of this test. We will demonstrate the feasibility of obtaining the samples for this test with minimally invasive methods. Finally we will validate the refined gene ratio prognostic test in an independent cohort of MPM patients from whom tumor and outcome data will be collected prospectively. We will determine the accuracy of this test in predicting outcome as defined by survival and tumor progression.